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Rituximab combined with belimumab for adult ITP
Results
Baseline characteristics
We included 15 patients (12 females) with median age 50 years (range, 20-70 years). All patients had previously received corticosteroids and/or IVIg (n=8) as first-line treatment, and ten had received a second-line treatment (Table 1). All but one had a previous transient response to corticosteroids. Within 1 month prior to inclusion, the median platelet count nadir was 16x109/L (range, 3-28 x109/L). All but one patient had cutaneous bleeding mani- festations and four had mucosal bleeding. Six patients had positive anti-nuclear antibody titers >1/160 with no fea- tures of systemic lupus erythematosus. When receiving the first RTX infusion, the median duration of ITP was 11 months (range, 4-52 months). Nine (60%) patients had persistent ITP and six (40%) had chronic ITP.
Safety
Overall, 31 adverse events were reported during the study (Table 2); five were infusion-related reactions during the first RTX administration (all grade I according to the CTCAE classification). No infusion-related reaction was reported with belimumab. All but one of 26 adverse events occurring during the study were grade I, and eight were possibly related to treatment (bronchitis, n=2; nasopharyngitis, n=3; arthralgia, n=1; candida vulvo- vaginitis, n=1; cystitis, n=1). One patient experienced grade II serum sickness with moderate arthralgia and rash one day after the second infusion of RTX.
γ-globulin levels were systematically monitored during the study (Figure 1A to D). We observed no severe infec- tion and no severe hypogammaglobulinemia (total serum immunoglobulin (Ig) <4 g/L or IgG <4.5 g/L). We observed a significant decrease in IgG and IgM titers (Figure 1; Online Supplementary Table S2) between baseline and W24 (0,98 g/L and 0,42 g/L decrease in median IgG and IgM titers, respectively). One patient experienced moderate hypogammaglobulinemia (total serum Ig titers 4.9 g/dL,
IgG 4.7 g/L) at W12, which was transient and recovered at W24. One patient had IgM titers <0.4 g/dl at W12 (IgM baseline 0.7 g/L) that did not recover at W52. IgA titers did not vary throughout the study.
Efficacy
Thirteen (86.7%) patients achieved an initial overall response at W12, including nine (60%) with CR (Figure 2). Two patients had a response at W7 and W8, respectively; other patients achieved a response after W4. One non- responder had bleeding symptoms at W4 and required thrombopoietin receptor agonists at W6. No other patient required ITP-directed therapy until W30. Among initial responders (R), one relapsed at W30, with moderate bleeding (cutaneous), and one eventually achieved CR at W36. At W52, the median platelet count among respon- ders was 189x109/L (range, 69-416x109/L) and 12 of 15 (80%) patients achieved overall response (95% Confidence Interval [CI]: 52-96), including ten (66.7%) with CR (95% CI: 38-88). After a follow-up of 18 months, one patient with an initial CR eventually relapsed at 16 months (Online Supplemental Figure S3).
Vaccine response
All patients had received vaccination with pneumococ- cal polysaccharide vaccine (Pneumovax-23®, n=2) or con- jugate vaccine PCV13 (Prevenar 13®, n=13) at least 15 days before inclusion (range, 15-90 days). When considering a protective threshold ≥1 μg/mL for anti-pneumococcal antibodies,13 13 patients were protected for at least 11 of the 13 serotypes tested (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F), and two patients (who had received Prevenar 13®) were protected for eight serotypes at base- line (Online Supplementary Table S3). At W52, eight (53%) patients had no change (n=6) or <2 serotypes (n=2) loss in protection among the 13 serotypes tested. Two patients who were protected for eight serotypes at baseline had lost two and four other serotypes, respectively, at W52. Finally, five patients (30%) had lost protection for a medi-
Table 1. Baseline characteristics of patients with immune thrombocytopenia receiving rituximab and belimumab.
Age/Sex
25/F
29/F
42/F
51/F
31/F
57/F
39/F
33/F
70/F
66/M
66/M
20/F
50/M
54/F 4 57/F 4
ITP duration (months)
Bleeding manifestations
Cutaneous Cutaneous + mucosal No Cutaneous Cutaneous Cutaneous Cutaneous Cutaneous Cutaneous Cutaneous Cutaneous + mucosal Cutaneous Cutaneous + mucosal Cutaneous
Cutaneous + mucosal
Treatments received before inclusion
CST
CST
CST, IVIg, hydroxychloroquine CST, Dapsone
CST, IVIg
CST, IVIg
CST, hydroxychloroquine
CST, hydroxychloroquine
CST, hydroxychloroquine
CST, IVIg, dapsone, hydroxychloroquine CST, IVIg, dapsone
CST, IVIg, romiplostim
CST, IVIg
CST, eltrombopag
Nadir platelet count during the month before inclusion (x 109/L)
16 3 3 28 16 27 18 18 18 9 15 15 6 7
11 4 15 15 5 52 44 11 3 42 5 4 31
CST, IVIg, vinblastin, romiplostim, eltrombopag 17
CST: corticosteroids, IVIg: Intravenous immunoglobulin. F: female; M: male.
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